The present invention relates to a crystallized form of tritoqualine hydrochloride as well as to a method for obtaining same.
Tritoqualine, for which the chemical name is 7-amino-4,5,6-triethoxy-3-(4-methoxy-6-methyl-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinoline-5-yl)-3H-isobenzofuran-1-one is a molecule known for its assumed antihistaminic action; in particular this is an enzymatic inhibitor of L-histidine decarboxylase. It has been demonstrated recently that this activity was very low; on the other hand its activity on the H4 receptor has raised strong interest for a few years. In particular, this molecule was widely studied in the field of digestive inflammatory diseases and more particularly gastric and esophageal diseases.
It was also found that tritoqualine was of interest in the treatment of acute leukemias and in that of cystic fibrosis, chronic obstructive pulmonary disease (COPD) and exacerbation of asthma.
These various applications of tritoqualine have been the subject of many patents.
However, the optimum use of tritoqualine encountered various problems related to the intrinsic physicochemical properties of the molecule, and in particular its very low solubility (100 ppm in water at room temperature).
Various methods were used for increasing the solubility and therefore the bioavailability of tritoqualine, for example by passing from the stage of tritoqualine hydrochloride formed in situ by addition of hydrochloric acid to tritoqualine in solution. The latter has a half lifetime of a few hours in an aqueous solution. The molecule is split at the 2 asymmetrical carbon atoms between the isoquinoline ring (cotarnine) and the phthalic ring.
In spite of many tests, it has never been possible to isolate tritoqualine hydrochloride in a crystallized form, which would have given the possibility of greater reproducibility of the clinical studies conducted with this molecule and better control of the action of tritoqualine upon its administration to patients.